Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Organophosphate (OP) pesticides are likely to alter the regulation of blood pressure (BP) because (i) BP control centers in the brain stem utilize cholinergic synapses and (ii) the irreversible inhibition of acetylcholinesterase activity by OP's causes cholinergic stimulation in the CNS. This study used radiotelemetric techniques to monitor systolic (S), diastolic (D), mean (M) BP, pulse pressure (systolic-diastolic), heart rate (HR), core temperature (T(c)), and motor activity in male Long-Evans rats treated with the OP pesticide chlorpyrifos (CHP) at doses of 0, 5, 10, and 25 mg/kg (p.o.) at 15:00 h 10 and 25 mg/kg CHP led to parallel elevations in S-BP, M-BP, and D-BP within 2 h after dosing. BP increased 15-20 mmHg above controls and increases persisted throughout the night and into the next day. HR decreased slightly in rats administered 25 but not 10 mg/kg CHP. T(c) was reduced by treatment with 25 mg/kg CHP and then increased above controls the next day. Motor activity was reduced by treatment with 25 but not 10 mg/kg CHP. Pulse pressure was elevated by 2-4 mmHg for 40 h after exposure to 10 and 25 mg/kg CHP. The increase in BP without an increase in HR suggests that CHP increases total peripheral resistance and may alter the baroreflex control of BP. Cholinergic stimulation of the CNS may explain the initial effects of CHP on BP; however, the persistent elevation suggests an involvement of neurohumoral pressor pathways.
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PMID:Prolonged elevation in blood pressure in the unrestrained rat exposed to chlorpyrifos. 1077 58

Pyridostigmine bromide (PB), a reversible inhibitor of acetylcholinesterase (AChE), is used for the treatment of myasthenia gravis. PB has also been provided to military personnel for preexposure protection against potential soman release. The entry of PB into the brain is typically minimal, but recently published data in mice suggest that a brief forced swim stress increases the permeability of the blood-brain barrier to PB. From these results, PB administered under stressful conditions was proposed to induce long-lasting central cholinergic deficits, potentially explaining the neurological and neuropsychological symptoms presented by some Gulf War veterans. In undertaking to replicate these results in the Long-Evans rat, no evidence of a stress-potentiated central effect of PB, administered at doses up 5.0 mg/kg ip, was found. Three stress protocols were used: restraint, forced swim, or a combined restraint/forced swim. Wistar rats were also tested in some of the protocols to ensure that the results were generalizable across rat strains, and plasma corticosterone levels were measured to test the effectiveness of the stressors employed. In contrast to the previously reported findings in the mouse, stress significantly reduced the entry of PB into rat brain, as measured by reduced inhibition of AChE activity: a 12.5% reduction in whole brain AChE activity after treatment with 5.0 mg/kg PB under control conditions declined to 9% after stress exposure. It is apparent, therefore, that the interaction between stress and PB requires further study, and previous data should be reassessed before they are used as a basis for interpreting symptoms presented by veterans.
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PMID:Stressful manipulations that elevate corticosterone reduce blood-brain barrier permeability to pyridostigmine in the Rat. 1081 58

Effect of low-level exposure of quinalphos (QP) and cypermethrin (CP) on the blood-brain barrier (BBB) permeability to macromolecular tracers, Evans blue (EB) and horseradish peroxidase (HRP) was studied in developing rat pups. Ten-day-old rat pups were daily exposed to QP and CP at a dose of approximately 1/50th of adult LD50 through oral intubation, upto postnatal day 17 (PND). Functional integrity of the BBB was assessed by measuring the brain uptake index (BUI) of HRP and by visually grading the brains of control and treated rat pups for the staining of EB. Our results have demonstrated a significant increase in the BUI for HRP (204 and 254%) and have also shown a significant amount of EB staining in QP and CP exposed brains, respectively, as compared to the age-matched controls. Studies carried out with the nitric oxide synthase (NOS) inhibitor L-NAME (30 mg/kg, i.p., on alternate days from PND 10-17) have provided significant protection against the QP-induced increase in the BBB permeability, suggesting the possible involvement of NO in the barrier disruption. Microvessel acetylcholinesterase activity was also inhibited (53%, P<0.001) in QP-exposed rat pups only, with no change observed in CP-exposed microvessels. However, membrane fluidity was found to be decreased in both QP (18%, P<0.05) and CP (15%, P<0.05) exposed microvessels compared to controls. It is evident from the study that QP and CP exposure during early postnatal period causes significant impairment in the development and maturation of the BBB that may have adverse consequences on the normal brain functioning with long-term neurotoxic effects.
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PMID:Effect of quinalphos and cypermethrin exposure on developing blood-brain barrier: role of nitric oxide. 1086 65

Long-lasting central nervous system (CNS) neurotoxicity of 4-tert-butyltoluene (TBT) has been investigated using electrophysiology, behaviour, and neurochemistry in Long Evans rats exposed by inhalation to 0, 20, or 40 p.p.m. TBT 6 hr/day, 7 days/week for 4 weeks. Flash evoked potentials and somatosensory evoked potentials were not affected by TBT. In Auditory Brain Stem Response there was no shift in hearing threshold, but the amplitude of the first wave was increased in both exposed groups at high stimulus levels. Three to four months after the end of exposure, behavioural studies in Morris water maze and eight-arm maze failed to demonstrate any TBT induced effects. Exposure was followed by a 5 months exposure-free period prior to gross regional and subcellular (synaptosomal) neurochemical investigations of the brain. TBT reduced the NA concentration in whole brain minus cerebellum. Synaptosomal choline acetyltransferase activity increased and acetylcholinesterase activity was unchanged suggesting increased synaptosomal ability for acetylcholine synthesis. The relative and total yield of synaptosomal protein was reduced suggesting reduced density and total number of synapses in situ, respectively. We hypothesise that a reduced yield of synaptosomal protein reflects a more general effect of organic solvent exposure on the software of the brain. The synaptosomal concentration per mg synaptosomal protein and the total amount of 5-hydroxytryptamine were not affected whereas the total amount of synaptosomal noradrenaline decreased. The concentration and the total amount of synaptosomal dopamine decreased. The noradrenergic and dopaminergic parts of CNS may be more vulnerable to TBT than the serotonergic, and these long-lasting effects may cause or reflect TBT-compromised CNS function.
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PMID:Four weeks' inhalation exposure of Long Evans rats to 4-tert-butyltoluene: effect on evoked potentials, behaviour, and brain neurochemistry. 1098 10

It is often assumed that cognitive function is more sensitive to neurotoxic chemicals than are the unconditioned behaviors employed in neurobehavioral screens; however, direct comparisons of the sensitivity of these test methods are lacking. The present studies were conducted to compare the effects of the widely used cholinesterase-inhibiting insecticide, chlorpyrifos (O,O'-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), on a visual signal detection task (SDT) with its effects on a neurobehavioral test battery. Adult male Long-Evans rats were trained to perform the SDT, dosed with CPF, and then assessed with both test instruments. Oral CPF (50 mg/kg) impaired signal detection for 8 days, and subcutaneous CPF (250 mg/kg) did so for 4 weeks. CPF (30 and 50 mg/kg po and 250 mg/kg sc) also lowered activity in the test battery for up to 18 days. Thus, CPF impaired attention and altered behavior in the test battery in the same dose ranges under two very different dosing scenarios.
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PMID:Comparing cognitive and screening tests for neurotoxicity. Effects of acute chlorpyrifos on visual signal detection and a neurobehavioral test battery in rats. 1127 74

After an acute (4 h) treatment with an irreversible cholinesterase inhibitor organophosphate, metrifonate (100 mg/kg i.p.), the activities of both acetyl- and butyrylcholinesterase were inhibited (66.0-70.7% of the control level) in the rat brain cortex and hippocampus. There were no significant changes in the acetyl- and butyrylcholinesterase activities in the olfactory bulb, or in the choline acetyltransferase activity in all three brain areas. After chronic (2 or 5 week) metrifonate treatment (100 mg/kg daily i.p.), the activities of both cholinesterases were substantially inhibited in the rat brain cortex and hippocampus (15.8-31.8% of the control levels), but there was no inhibition of the choline acetyltransferase activity. Moreover, chronic metrifonate treatment did not have any effect on the distribution of the acetylcholinesterase molecular forms. In vitro, metrifonate proved to be a more potent inhibitor of butyryl- than of acetylcholinesterase in both the cortex and the hippocampus. In the hippocampus, the butyrylcholinesterase activity was twice as sensitive to metrifonate inhibition as that in the cortex (IC50 values 0.22 and 0.46 microM, respectively). The effects of chronic (5 week) metrifonate treatment on the blood-brain barrier of the adult rat were examined. The damage to the blood-brain barrier was judged by the extravasation of Evans' blue dye in three brain regions: the cerebral cortex, the hippocampus, and the striatum. No extravasation of Evans' blue dye was found in the brain by fluorometric quantitation. These data indicate that chronic metrifonate treatment may increase the extracellular acetylcholine level via cholinesterase inhibition, but it does not have any effects on the blood-brain barrier. Therefore, it appears reasonable to hypothesize that cholinesterase activities do not play a role in the blood-brain barrier permeability.
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PMID:Effects of chronic metrifonate treatment on cholinergic enzymes and the blood-brain barrier. 1131 45

Previous studies have shown that moderate to high levels of chlorpyrifos (CPF) alter cognitive function in adult and immature rats. In the present study, we tested the hypothesis that lower-level exposure to CPF before or immediately after weaning causes deficits in cognitive function. A total of 78 Long-Evans rats were injected subcutaneously with 0, 0.3 or 7.0 mg/kg CPF every 4 days before or after weaning and were tested with the Morris swim task from postnatal day 24 through 28. Exposure to CPF before weaning did not cause signs of overt cholinergic intoxication or impaired growth nor did the exposures cause significant inhibition of regional brain cholinesterase (ChE) activity or reduction in muscarinic receptors 24 h after the last injection. However, spatial learning was impaired after 5 days of training in the group of weanling rats administered 7.0 mg/kg CPF. Rats administered 0.3 or 7.0 mg/kg CPF after weaning were also impaired in the task, without significant changes in brain ChE activity. These data indicate that low-level exposure to CPF caused deficits in cognitive function in weanling rats, and these effects did not appear to be mediated by the inhibition of brain ChE. It is suggested that the alteration of cognitive function in juvenile rats is an important functional correlate of the cellular and molecular effects of CPF in the immature brain. The mechanisms for CPF-induced cognitive dysfunction are unknown.
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PMID:Cognitive function and cholinergic neurochemistry in weanling rats exposed to chlorpyrifos. 1144 24

Our laboratory has found that the organophosphate pesticide chlorpyrifos elicits an elevation in blood pressure that persists for approximately 24 hr after exposure. Since organophosphate pesticides inhibit acetylcholinesterase activity and cause cholinergic stimulation in the central nervous system and peripheral tissues, we suspect that the hypertensive response from chlorpyrifos is elicited by activation of pressor areas in the brain stem, specifically muscarinic receptors which are known to mediate hypertensive responses. Oxotremorine, a muscarinic agonist, should elicit a blood pressure response similar to organophosphate pesticides. This study used radiotelemetry to assess the effects of oxotremorine on blood pressure, heart rate, core temperature, QA interval (a measure of cardiac contractility), and motor activity in the male, Long-Evans rat. Subcutaneous co-administration of 0.2 mg/kg oxotremorine with 1.0 mg/kg methyl scopolamine (i.e., to block oxotremorine's peripheral effects) caused a marked elevation in blood pressure that developed concomitantly with a 2 degrees decrease in core temperature, 60 beats/min. increase in heart rate, increase in cardiac contractility but no change in motor activity. Overall, blood pressure increased by 19 mmHg from baseline and the response persisted for approximately 12 hr after injection. Methyl scopolamine alone increased heart rate but had no effect on blood pressure, core temperature, and motor activity. Oxotremorine injected without methyl scopolamine led to a relatively minor increase in blood pressure and hypothermia. Overall, central muscarinic stimulation with oxotremorine and methyl scopolamine leads to a vigorous hypertensive response that is associated with increased cardiac contractility, suggesting an increase in cardiac output. Combined central and peripheral cholinergic stimulation following oxotremorine without methyl scopolamine, as would also occur with exposure to chlorpyrifos and other organophosphate pesticides, did not elicit as much of a hypertensive response. This would suggest pathways other than those controlled directly with muscarinic receptors are operative in the development of chlorpyrifos-induced hypertension.
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PMID:Peripheral versus central muscarinic effects on blood pressure, cardiac contractility, heart rate, and body temperature in the rat monitored by radiotelemetry. 1148 8

Sex hormones may exert neuroprotective effects in various models of brain lesions. Male and female Long-Evans rats were subjected to intracerebroventricular injections of 2 microg 192 IgG-saporin or vehicle. Starting 2 days before surgery, half the male rats were treated with estradiol for 7 days. Three weeks after surgery, they were sacrificed for histochemical staining of acetylcholinesterase (AChE) and densitometric evaluations. The lesion induced a substantial to dramatic decrease of the AChE-positive fiber density in the cingulate, somatosensory, piriform, retrosplenial and perirhinal cortices, and in the hippocampus. Weak effects were found in the striatum. There was no significant decrease in the dorsal thalamus. Sex had no significant effect on AChE-positive staining in any brain area. In males, estradiol treatment did not alter the effects of 192 IgG-saporin. These results show that sex or estradiol treatment in male rats does not interfere with the immunotoxic effects of intracerebroventricular injections of 192 IgG-saporin on cholinergic projections from the basal forebrain.
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PMID:Effects of 192 IgG-saporin on acetylcholinesterase histochemistry in male and female rats. 1212 15

Adult male Long-Evans rats were subjected to bilateral lesions of the cholinergic neurons in the nucleus basalis magnocellularis (NBM) by injection of 0.2 or 0.4 microg 192-IgG-saporin in 0.4 microl phosphate-buffered saline. Control rats received an equivalent amount of phosphate-buffered saline. Starting 2 weeks after surgery, all rats were tested for locomotor activity in their home cage, beam-walking performance, T-maze alternation rates (working memory), reference and working memory performance in a water-maze task, and memory capabilities in the eight-arm radial maze task using uninterrupted and interrupted (delay of 2 min, 2 h and 6 h after four arms had been visited) testing procedures. Histochemical analysis showed a significant decrease of acetylcholinesterase (AChE)-positive reaction products (30-66%) in various cortical regions at the 0.2-microg dose. At the dose of 0.4 microg, there was an additional, although weak, damage to the hippocampus (17-30%) and the cingulate cortex (34%). The behavioral results showed only minor impairments in spatial memory tasks, and only during initial phases of the tests (reference memory in the water maze, working memory in the radial maze). The behavioral effects of the dramatic cholinergic lesions do not support the idea of a substantial implication of cholinergic projections from the NBM to the cortex in the memory processes assessed in this study, but they remain congruent with an involvement of these projections in attentional functions.
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PMID:Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats. 1217 91


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